This invention generally pertains to heterocyclic carbon compounds having drug and bio-affecting properties and to their preparation and use. In particular, the invention is concerned with disubstituted piperidine derivatives wherein one substituent is an acyclic amide moiety linked by a bridging alkyl connector to one of the carbon ring positions of the piperidine ring and the other substituent is a pyrimidinyl ring system attached to the piperidine nitrogen atom. The compounds of this invention are cerebral function enhancers useful, for example, in treating various dementias due to degenerative processes as well as in enhancing memory and learning.
Clinical aspects of various degenerative dementias, as well as the socioeconomic problems they cause in affected populations, are well known to those skilled in the art. One will also appreciate that various drug treatments of these disorders are currently under study. Among such drugs are a class of drugs known as nootropic agents or, more commonly, cognition enhancers; some of which are currently undergoing clinical evaluation in patients diagnosed as having Alzheimer's disease, a serious and fairly common CNS disorder of the elderly. Many of these drugs under clinical study are members of a class of N-substituted 2-pyrrolidinone derivatives of structure ##STR2## a: X=H; R=CH.sub.2 CONH.sub.2 (piracetam) b: X=OH; R=CH.sub.2 CONH.sub.2 (oxiracetam)
c: X=H; R=CH.sub.2 CONH[CH.sub.2 ].sub.2 N[CH(CH.sub.3).sub.2 ].sub.2 (pramiracetam) ##STR3## For a representative reference describing the testing and properties of a member of this series 1, see Butler, et al., J. Med. Chem., 27, pages 684-691 (1984). Preliminary clinical results with this class of agents, exemplified by structures 1a-d, indicate that these drugs may have some beneficial effects in treating senile dementias in the elderly.
Related art may be viewed in light of the following general structural formula (2). ##STR4## wherein X is usually C.sub.2-4 substituted or unsubstituted alkylene; Y is carbonyl or methylene; A is a bridging moiety such as alkylene, alkanoyl, alkyleneamidoalkylene, and the like; W is nitrogen; and B is a pyrimidinyl, pyridinyl, or benzisothiazolyl ring system. Members of this series are reported to have psychotropic, anxiolytic, antiemetic, tranquilizing, cognitive enhancing, as well as other nootropic activities. For more detailed disclosure of these compounds, see: Yevich and Mattson, U.S. Pat. No. 4,668,687 issued May 26, 1987, Wu, et al., U.S. Pat. No. 3,717,634 issued Feb. 20, 1973; Temple, U.S. Pat. No. 4,423,049 issued Dec. 27, 1983; and New and Yevich, U.S. Pat. No. 4,524,206 issued Jun. 18, 1985.
Other subject matter related to formula 2 compounds was disclosed by Malawska, et al., in "Synthesis and Pharmacological Properties of Some 2-Pyrrolidinone Mannich Bases" in the Polish Journal of Pharmacology, 34, pages 373-382 (1982). They described a series of compounds, of which one subclass is represented by structural formula 3, which reportedly display analgesic properties as well as weak anti-inflammatory action. ##STR5## wherein X is hydrogen or chlorine.
The most relevant art is believed to be the patent to Mattson, et al., U.S. Pat. No. 4,826,843 issued May 2, 1989, wherein compounds of general formula 4 were disclosed as having cognition and memory enhancing activities. ##STR6##
For Formula 4, X is an ethylene chain or 1,2-benzo ring; Y is carbonyl or methylene; R.sup.1 is hydrogen or lower alkyl; and Z is an R.sup.2, R.sup.3 -disubstituted diazinyl ring selected from pyridazine, pyrimidine, and pyrazine ring systems.
Mattson, et al., U.S. Pat. No. 5,098,904 issued Mar. 24, 1992 disclosed and claimed oxygenated derivatives of the formula (4) compounds.
The art compounds, as set forth supra, incorporate a lactam or lactim ring moiety at the compound's non-diazine terminus. The novel acyclic amide compounds described herein are structurally distinct cerebral function enhancing agents. There are no teachings in the art which would make these specific compounds of the instant invention anticipated or obvious.